Combination therapy of avutometinib and MRTX1133 synergistically suppresses cell growth by inducing apoptosis in KRASG12D-mutated pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma is a lethal malignancy with a poor prognosis, and more than 90% of pancreatic ductal adenocarcinoma cases involve activating mutations in the oncogene KRAS. Therapeutic strategies that inhibit the mitogen-activated protein kinase pathway, a critical effector pathway in KRAS-mutated cancers, have garnered significant attention. Among several molecular-targeted drugs, avutometinib [CKI27(2)/CH5126766/RO5126766/VS-6766], a novel dual RAF/MEK clamp, shows promise for patients with KRAS-mutated cancers. However, its efficacy as a single agent remains insufficient, highlighting the need for more effective treatment strategies. In this study, we found that avutometinib alone was insufficiently effective against pancreatic cancer cells with the KRASG12D mutation. In these cells, combining avutometinib with the KRASG12D inhibitor MRTX1133 demonstrated synergistic inhibitory effects on cell growth. We further investigated the efficacy of this combination therapy in in vitro and in vivo experiments. In these experiments, the combination therapy upregulated BIM, downregulated survivin, and induced apoptosis in pancreatic cancer cells with the KRASG12D mutation. In in vivo experiments, the combination therapy markedly delayed tumor growth compared with either therapy alone. Therefore, the combination of avutometinib and MRTX1133 may represent a promising therapeutic approach for KRASG12D-mutated pancreatic cancer.